The incidence of fungal infections is steadily rising as a consequence of antibiotic treatments, an immunosuppressed or immunocompromised population (mainly caused by cancer treatment, HIV, allergy-treatments, transplantations and general surgery) and an aging population.
Currently, an estimated 15,000 allogenic and 25,000 autologous stem cell transplants are performed worldwide yearly. In addition, from 1998 to 2002, 113,682 solid organ transplants were performed in the United States, which is a 20% increase over the previous 5-year period. Unfortunately, patients undergoing these life-saving procedures are at increased risk for fungal infections for example by Aspergillus fumigatus and other Aspergillus spp. due to their immuno-compromised condition. Additionally the populations of immuno-compromised patients due to HIV, cancer therapy, surgical non-transplants and general ageing also continue to increase and with it the number of cases of severe fungal infections for example systemic candidiasis. Candida species account for 80% of infections in general medicine, 40% in HIV populations and 90% in both cancer therapy and surgical-non transplant cases. Candida is now the 4th largest cause of nosocomial blood stream infections.
Mortality from systemic fungal infections remains high despite the development of new antifungal agents, and Candida bloodstream infections in the United States are associated with a 40% crude mortality rate. Overall, since 1980, the mortality due to Aspergillus fumigatus has increased 357% and is continuing to increase.
Furthermore, during the last decade, there have been changes in the epidemiology of these systemic infections, with five species (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) responsible for more than 90% of invasive infections due to Candida Candida spp. are the fourth most common cause of nosocomial bloodstream infections, and while C. albicans was the predominant cause of Candida bloodstream infections in the early 80s, C. glabrata has emerged as the second most common cause in various part of the world, including the United States.
In addition to Aspergillus and Candida infections, other fungal pathogens such as Zygomycetes, Fusarium and Scedosporium spp. are becoming increasingly important. Their susceptibility to existing antifungals is limited and their mortality rate is ≧70% in patients with hematological malignancies. In other patients the mortality rates vary between 30 and 80%.
Onychomycosis is a fungal infection of the nails which is estimated to affect 2-13% of the general US population and up to 25% of the geriatric and diabetic populations. Common risk factors include age, male gender, diabetes, nail trauma, and chronic Tinea pedis (fungal infection of the foot). Onychomycosis has significant cosmetic, psychological and social implications. In some patient subsets it has serious medical consequences (e.g. foot amputations in diabetics).
Currently the infection is primarily treated with oral drugs, but this is not desirable for what is normally a non life threatening infection, as the currently used antifungal drugs have significant toxicities. It also leads to poor compliance—multiple surveys have shown it is counter intuitive to patients to take a pill for c. 6 months to treat a toe nail infection, especially given there is no visible improvement for the first 2-3 months of treatment. Ideally a fast acting topical approach is desired but existing topical drugs have very poor efficacy due to the difficulty of reaching the fungi that are located under the nail. Ciclopirox nail lacquer is the only FDA-approved topical agent available in the US for the treatment of onychomycosis, while amorolfine is a topical agent available in Japan and in Europe. However, these nail lacquer products have very limited efficacy in part because of their inability to penetrate to the nail bed where the infection resides, but also due to the nature of the compounds. As a result of these limitations, only 14% of onychomycosis patients are currently treated with topical drug and just 7% receive systemic drug therapy. In addition, there is a >25% recurrence rate amongst “cures”.
At present there are four major compound classes available for the treatment of fungal infections. They are listed in Table A. The use of these drugs may in some cases of fungal infection deliver reasonable results, however, as outlined above mortality caused by fungal infections is still high. Apart from insufficient efficacy there are furthermore several other problems associated with the existing drugs:                Significant toxicity and/or patient sensitivity to the existing drugs e.g. liver toxicity is associated with many of the existing compounds (a significant problem, in particular due to the extended length of treatments) and Lamisil has cardiac toxicity.        Many pathogenic strains are insensitive or resistant against the anti-fungal drugs and resistance development is also of concern.        High relapse rate        
In addition in many cases the efficacy rate is poor.
In relation to treatment of certain fungal infections such as onycomycosis, additional problems are associated with the existing drugs:                Long onset to relief of symptoms        Long treatment and compliance regimes are necessary, leading to problematic compliance        
Additionally, drug interactions are a common problem. In particular, azoles are cytochromes P-450 inhibitors, which may result in that these compounds cannot be administered to a patient receiving medication, the action of which is dependent on cytochrome P-450 activity.
Antifungals currently available for the treatment of systemic infections include Amphotericin B and its less toxic lipid formulations, e.g. AmBisome, and the echinocandins, which include Anidulafungin, Caspofungin, and Micafungin, all of which must be administered intravenously. Along with fluconazole, the newer triazoles such as Posaconazole (oral) and Voriconazole (oral and intravenous) are FDA approved for the treatment and prevention of systemic Candida infections. Despite these new additions to the antifungal armamentarium, treatment failure is still unacceptably high and there is an increase in resistance development to the azole and echinocandin families of drugs.
Caspofungin resistance is still an uncommon occurrence with c. 8% of C. tropicalis and c. 2% of C. glabarata isolates having been defined as resistant (MIC values of >2 mg/L). Nevertheless, taking into consideration the recent introduction of this drug and the observation that 2001-2004 surveillance studies identified >99.5% of patients as Caspofungin sensitive, it is disconcerting how rapidly echinocandin resistance is spreading. Furthermore, there have recently been reported cases of reduced C. glabarata susceptibility developing during Caspofungin therapy. The target of Caspofungin is the enzyme 1,3-β-D-glucan synthase, encoded by one of several FKS genes, depending on the species. It has been shown that in clinical isolates, mutations in the FKS 1 gene resulting in amino acid changes in the protein were necessary and sufficient to confer reduced susceptibility to Caspofungin. Recently Candida spp. with reduced susceptibility to the newer members of the echinocandin family have also been reported.
In terms of resistance, for the azoles alone, three different resistance mechanisms have been identified: a) alternative pathways for the synthesis of cell membrane sterols, b) mutations in the target demethylase site and c) increased efflux of drug from the fungal cell.
TABLE ASummary of existing anti-fungal drug classes and modes of actionDrug ClassMode of ActionPolyene anti-fungalsA molecule with a cyclic part, the(e.g. Amphotericin B)molecule consisting of a hydrophobic andhydrophilic region. The polyeneantimycotics bind with sterols in thefungal cell membrane, principallyergosterol. This changes the transitiontemperature of the cell membrane from afluid to a more crystalline state. Animalcells contain cholesterol instead ofergosterol and so they are lesssusceptible.Imidazole and triazoleThe imidazole and triazole anti-fungalanti-fungalsdrugs inhibit the enzyme cytochrome(e.g. Fluconazole orP450 14α-demethylase. This enzymeItraconazole)converts lanosterol to ergosterol, and isrequired in fungal cell membranehomeostasis. These drugs also blocksteroid synthesis in humans.AllylaminesAllylamines inhibit the enzyme squalene(e.g. Terbinafine)epoxidase, another enzyme required forergosterol synthesis.EchinocandinsEchinocandins inhibit the synthesis of(e.g. Caspofungin)glucan in the cell wall, probably via theenzyme 1,3-β glucan synthase.
Anti-fungals work by exploiting differences between mammalian and fungal cells to selectively inhibit growth or to kill the fungal organism preferably without dangerous effects to the host. Unlike bacteria, both fungi and humans are eukaryotes. The basic structure of fungal cells and human cells is similar. This means it is more difficult to find a target for an anti-fungal drug that does not also exist in the infected organism. Consequently, there are often side-effects to some of these drugs. Some of these side-effects can be life-threatening if the drug is not used properly.
Well established examples of the toxicity problems are the nephrotoxicity of Amphotericin B, the liver damage caused by Terbinafine and the generalized intolerance against azoles. For example, up to 20% of females with vaginal candidiois cannot tolerate Fluconazole.
U.S. Pat. No. 6,541,506 describes methods for the synthesis and use of enediynes (compounds with a double bond and two triple bonds, in a given order.) The patent describes that these compounds may inhibit fungal infections and possibly also inhibit growth of fungal cells.
In agriculture, yield losses caused by various fungal pathogens in crops and other plants (for example, ornamental and amenity grasses) are significant, particularly across the major groups of fungal diseases such as rust, rot (root and fruit), leaf spots, mildews and wilts.
To date however, there has been no discovery of an effective antifungal agent for systemic or topical use, lacking the drawbacks of existing antifungal drugs.